Alain Volant

Loss of heterozygosity at chromosome arm 13q and RB1 status in human prostate cancer.

Aberrations of the long arm of chromosome 13 are common in prostate cancer and were initially attributed to alterations of the RB1 gene in band q14 of the chromosome. However, prostate tumors generally yield normal p110RB1 nuclear staining despite loss of heterozygosity (LOH) at the RB1 locus. Our previous analysis of chromosome arm 13q showed allelic loss in 41% of primary prostate tumors. To refine our knowledge of 13q, we extended our previous LOH study by using more polymorphic markers to analyze more prostate tumors. Sixty human prostate carcinomas were screened for allelic loss on 13q by using 13 13q-specific markers. LOH on the long arm of chromosome 13 was found in 39 (65%) of the 60 tumors. Furthermore, 33 of these 39 tumors had evidence of allelic loss involving a region of 13q14 containing RB1. Because immunohistochemical assessment of pRb expression is controversial in prostate tumors, we used a quantitative reverse transcription polymerase chain reaction (RT-PCR) method to determine whether RB1 is the target tumor suppressor gene in this region. RB1 mRNA steady-state levels were determined in 12 prostate tumors preselected on the basis of presumed deletion at the RB1 locus and four prostate tumors without LOH at the RB1 locus; five normal prostate specimens were used as controls. One of the 12 assessable prostate tumors with presumed LOH at RB1 showed a corresponding decreased in RB1 mRNA expression, whereas none of the four tumors without LOH at RB1 locus showed such a decrease. This study, based on another technical approach, confirms that RB1 is not the main target of the observed LOH at 13q14.3, and raises the possibility that another tumor suppressor gene in this region plays a key role in prostate cancer.

Testicular adrenal rest tumours in salt wasting congenital adrenal hyperplasia (in vivo and in vitro studies).

We describe the case of a 20-year-old patient with salt-wasting congenital adrenal hyperplasia (CAH) related to 21-hydroxylase deficiency. Bilateral craggy testicular tumours were found, requiring histological evaluation. Prior to the surgical procedure, the patient was treated with dexamethasone (he presented cortisol deficiency) and was stimulated with ACTH. High levels of 11beta-OH steroids measured in the gonadal vein, compared with peripheral blood samples suggested the presence of adrenal rests. Incubation of the tumours (which could not be differentiated histologically, from Leydig tissue), with radioactive steroid precursors was carried out. The results revealed the testicular tumours were of adrenal tissue origin, associated with 21-hydroxylase deficiency. The patients non-compliance to glucocorticoid treatment was the main cause of his hypogonadotropic hypogonadism.

Prognostic value of initial fluorodeoxyglucose-PET in esophageal cancer: a prospective study.

ObjectivesEsophageal cancer outcome greatly depends on the pathological stage. Our objectives were to assess prognosis on the basis of the initial fluorodeoxyglucose (FDG)-PET scan, focusing on the correlation between overall survival and FDG uptake in the primary, as well as the presence of FDG-positive lymph nodes or distant metastases. MethodsFifty-two esophageal cancer patients undergoing FDG-PET as part of initial routine staging procedure before treatment were included. The maximum standardized uptake value (SUVmax) was determined in each primary lesion and the number of abnormalities including primary, lymph nodes, or distant metastases was recorded. Correlation with overall survival was performed using Kaplan–Meier method and Cox regression analysis was used to assess the prognostic value of PET parameters. ResultsHalf of the patients were planned for initial curative surgery (52%). Using univariate survival analysis, either surgery, SUVmax >9, two or more PET abnormalities or the presence of FDG-positive nodes were significant overall survival prognostic predictors. After multivariate analysis, only SUVmax >9 and FDG-positive lymph nodes were found as independent predictors of poor outcome. ConclusionIn this prospective study, FDG-PET was found to provide prognostic information supporting a new indication for initial FDG-PET examination in esophageal cancer.

Nephrogenic Adenoma of the Bladder in Renal Transplant Recipients: A Report of 9 Cases with Assessment of Deoxyribonucleic Acid Ploidy and Long-Term Followup

PURPOSE We evaluated the outcome of nephrogenic adenoma, a benign tumor rarely encountered in renal transplant recipients. MATERIALS AND METHODS Between 1985 and 1993, 9 renal transplant recipients with a nephrogenic bladder adenoma removed by endoscopic resection were followed for 24 to 88 months (mean 40). Tumor deoxyribonucleic acid ploidy was assessed by flow cytometry at diagnosis and/or relapse. RESULTS The relapse rate was 88%. The tumors were diploid and of low proliferating potential, and showed no malignant transformation. CONCLUSIONS Our study confirms the lack of premalignant potential of nephrogenic adenomas. However, since transplant recipients might be at increased risk for bladder cancer, they should be followed closely.

A Gene Expression and Pre-mRNA Splicing Signature That Marks the Adenoma-Adenocarcinoma Progression in Colorectal Cancer

It is widely accepted that most colorectal cancers (CRCs) arise from colorectal adenomas (CRAs), but transcriptomic data characterizing the progression from colorectal normal mucosa to adenoma, and then to adenocarcinoma are scarce. These transition steps were investigated using microarrays, both at the level of gene expression and alternative pre-mRNA splicing. Many genes and exons were abnormally expressed in CRAs, even more than in CRCs, as compared to normal mucosae. Known biological pathways involved in CRC were altered in CRA, but several new enriched pathways were also recognized, such as the complement and coagulation cascades. We also identified four intersectional transcriptional signatures that could distinguish CRAs from normal mucosae or CRCs, including a signature of 40 genes differentially deregulated in both CRA and CRC samples. A majority of these genes had been described in different cancers, including FBLN1 or INHBA, but only a few in CRC. Several of these changes were also observed at the protein level. In addition, 20% of these genes (i.e. CFH, CRYAB, DPT, FBLN1, ITIH5, NR3C2, SLIT3 and TIMP1) showed altered pre-mRNA splicing in CRAs. As a global variation occurring since the CRA stage, and maintained in CRC, the expression and splicing changes of this 40-gene set may mark the risk of cancer occurrence from analysis of CRA biopsies.

Trends in incidence, management, and survival of gastric and cardia carcinomas in the area of Finistere (France) between 1984 and 2003

Objective The aim of this study was to evaluate trends in incidence and prognosis of gastric and cardia carcinomas in the area of Finistère (France) between 1984 and 2003. Methods The Digestive Tumor Registry of Finistère recorded all new cases of gastric and cardia carcinomas from January 1, 1984 to December 31, 2003. Raw incidence data were standardized using the direct method based on the reference world population. The data and survival rates were studied in univariate and multivariate analyses. Results Between 1984–1988 and 1999–2003 the standardized incidence of distal gastric carcinomas decreased (10.74±0.39–5.68±0.27/year/100 000 inhabitants, P<0.001). There was no significant increase in the incidence of cardia carcinomas (0.83±0.11–1.25±0.14/year/100 000 inhabitants). The frequency of macroscopically infiltrating tumors doubled (P<0.001) and linitis plastica increased from 9 to 16.2% (P<0.001). Overall survival rates increased only for patients with metastatic carcinomas of both locations (P<0.001) and with advanced tumors of distal stomach (P<0.001) receiving therapy. Conclusion This study showed a significant decrease over time in the incidence of distal gastric carcinomas but no significant increase in the incidence of cardia carcinomas. Despite improvement in the management of patients, prognosis remains dismal, probably because of an increased incidence of poor prognosis of histological and anatomical types.

Prevalence and topography of intestinal metaplasia in columnar lined esophagus.

OBJECTIVES Barretts mucosa is considered as a mosaic of three epithelial types but little is known about the topography of intestinal metaplasia in columnar lined esophagus. The aims of the study were to determine the prevalence of intestinal metaplasia within long and short segments of columnar lined esophagus and to analyze the distribution of the intestinal metaplasia within long segments of Barretts esophagus. PATIENTS AND METHODS The study was performed on the initial endoscopy carried out among 112 patients enrolled in an endoscopic surveillance program. Seventy-two patients with columnar mucosa extending more than 3 cm into the esophagus (group I) and 40 patients with a short segment of columnar mucosa (group II) had multiple biopsies according to a standardized protocol. 1163 biopsies were analyzed on the whole: 949 biopsies in group I and 214 biopsies in group II. RESULTS Intestinal metaplasia was identified among 650 (68.5%) and 50 (23.4%) biopsies in groups I and II respectively (P<10-7). The proportion of biopsies with foci of intestinal metaplasia increased significantly with the length of the columnar mucosa. The diagnosis of Barretts esophagus was confirmed in 100% of the patients in group I and in 45% of the patients in group II. In long segments of Barretts esophagus, intestinal metaplasia was more frequently observed in the 2 upper thirds of the columnar mucosa that in the lower third (P<10-7). Detailed mapping of the distribution of epithelial types within the columnar lined esophagus identified three patterns of distribution of intestinal metaplasia within long segments of Barretts esophagus: unifocal, multifocal and diffuse, in 5%, 56% and 39% of the patients respectively. Dysplasia was present in 15% of patients with long segments of Barretts esophagus and 11% of patients with short segments (NS). CONCLUSION The distribution of intestinal metaplasia within columnar lined esophagus is heterogeneous and three distinct patterns can be identified: unifocal, multifocal and diffuse. Considering the risk of sampling error, the current recommendations concerning the biopsy protocols are mandatory until the validation of new techniques such as chromoendoscopy or magnifying endoscopy.

Infrequent p16/CDKN2 alterations in squamous cell carcinoma of the oesophagus.

Loss of heterozygosity (LOH) on chromosome 9 and p16 (MTS1/CDKN2) gene mutations have been reported in various human cancers. The present study aimed to determine the prevalence of LOH in 100 oesophageal squamous cell carcinomas (OSCCs) by typing microsatellite loci and mutations of the p16 gene. The methods used included denaturing gradient gel electrophoresis (DGGE) and DNA sequencing of exon 2. LOH was found in 14.7% of the OSCC cases. Six gene alterations were identified in exon 2. They consisted of three deletions and the same polymorphism in three samples. The relatively low rate of p16 mutation compared with the frequency of LOH suggests the possible involvement of another tumour suppressor gene located on chromosome 9 in oesophageal carcinogenesis.

La recherche clinique en cancérologie digestive: de la cible à la véritable personnalisation du traitement?

From the strategic use of biology in clinical practice to new diagnostic tools, from the new targeted therapies associated with chemotherapy with controlled side effects, to increasingly accurate radiotherapy associated with increasingly optimised surgery, research in digestive oncology has clearly become multidisciplinary. The challenge now is to develop all these improvements at the same time and with a critical eye, and try to extend the recognized progress made in colorectal metastatic cancer to other digestive localisations whose prognoses are much less positive. In this respect, prevention, optimisation of treatment using predictive factors, management of elderly patients with digestive cancer, and economic optimisation of treatment are some of the challenges we must take up in the next few years if we are to obtain the main objective: truly personalised medicine.RésuméDe la biologie devenue stratégique en clinique aux nouveaux outils d’évaluation diagnostique, des nouvelles thérapeutiques ciblées couplées à une chimiothérapie aux effets secondaires contrôlés à la radiothérapie toujours plus précise associée à une chirurgie de plus en plus optimisée, la recherche clinique en cancérologie digestive est devenue clairement multidisciplinaire. Son challenge va être de développer ces avancées ensemble et avec un souci d’évaluation constant, d’essayer d’étendre les progrès connus dans le cancer colorectal métastatique aux autres localisations digestives au pronostic beaucoup plus défavorable. Dans ce cadre, la prévention et l’optimisation des traitements par l’aide de facteurs prédictifs, le développement de l’oncogériatrie et la dimension médicoéconomique seront parmi les grands challenges à relever ensemble.

Thérapies ciblées et cancers colorectaux : un traitement incontournable ?

Les therapies ciblees sont tres rapidement devenues un element indispensable dans la prise en charge des cancers colorectaux metastatiques. Leurs mecanismes d’action ont pour cible le VEGF ou le recepteur a l’EGF pour celles actuellement commercialisees. Cette revue de la litterature se propose d’etudier a travers les dernieres publications leurs taux de reponses, leurs effets secondaires et leur valeur ajoutee en combinaison avec les protocoles de chimiotherapies conventionnelles.